This invention relates to a biocompatible, non-inflammatory, collagen conjugate material, described herein in the form of a porous membrane structure, and to a process for making this material. While individual components of this system are known in the art and in the related literature, described herein is a novel composite material, able to alter and totally eliminate the mild, chronic cellular inflammatory response exhibited by purified bovine corium collagen. The novel conjugate collagen material herein described maintains its complete physical integrity for an extended period of time, up to at least 3 months, in the absence of any inflammatory response when implanted subcutaneously in animal models.
Collagen is used in medicine and dentistry in a variety of configurations and uses. Resorbable collagen suture material in the form of plain or chromic surgical gut is one of the most widely used surgical suture materials in the world. Within the last decade, Surgikos, a Johnson & Johnson Company, introduced the bovine collagen Artegraft to serve as a substitute segmental arterial replacement, as an arterial bypass, or as an arteriovenous shunt. In 1976, Avicon, Inc. introduced Avitene, an absorbable microfibrillar collagen hemostat for use in oral and general surgery. More experimental uses of collagen have included the use of collagen gels as a vitreous replacement in ophthalmologic surgery, and the use of reconstituted collagen membranes as a wound dressing in burn patients.
One repeatedly documented drawback to the use of collagen as a biomaterial is the consistent chronic cellular inflammatory response evident in both animal and human studies. Avitene, as described in its package insert, has been shown to stimulate a mild chronic cellular inflammatory response in both human and animal studies. The literature reports that collagen sutures are the most irritating and among those eliciting the greatest giant cell response; see Schluger, et. al., Periodontal Disease, pg 464, Lea & Febiger, 1978. This inflammatory response may result in residual scar tissue formation or even, in general surgery, in adhesion formation. This drawback must be compared with the advantages of this suture material, which include its monofilament-like structure resulting in ease of handling, uniform tensile strength, and uniform predictable rates of absorption.
The significance of this low-grade inflammatory response associated with the use of collagen as a biomaterial can be illustrated by some of the adversed reactions reported with its use. Avitene, for example, when placed in close approximation to the closure of skin incisions may interfere with the healing of skin edges. Adverse reactions associated with the Artegraft suture material include pseudointima formation and, less frequently, pseudodiaphragm formation. Disruption of anastomoses, especially in the presence of infection, has also been observed. In a few cases transient low grade fever, the etiology of which has not been obvious, has been experienced. The inflammatory reaction to the Artegraft collagen may be associated with the occasional true aneurysm reported with its use, since this inflammatory response may accelerate the degradation of the fibrous collagen making up the structural support of the Artegraft.
Clearly, it would be extremely advantageous for any biomaterial to be non-inflammatory. Few synthetic biomaterials possess this property. Since collagen possesses many worthwhile properties as a biomaterial, not the least of which is its structural similarity to native connective tissue, the elimination of the low-grade inflammatory response connected with its use would be highly desirable.
The other major component of the conjugate described herein is the enzyme alkaline phosphatase. When our experiments with the compexation of collagen-alkaline phosphatase membranes began, the intent was to induce calcification within these membranes as it has been hypothesized that alkaline phosphatase has some major role in calcification. Recently, a comprehensive review of all the literature concerning the structure and function of alkaline phosphatase has become available; see McComb, R. B., & Bowers, G. M., Alkaline Phosphatase, Plenum Press, New York, N.Y., 1979. In a section devoted to physiological functions of the enzyme, the authors state: "Although the hydrolytic functions of alkaline phosphatase have been intensively studied for more than 50 years, we have at this time no clear idea of the value of this enzyme to the organism."
While an increase in the alkaline phosphatase activity of host leukocytes is associated with an increase in phagocytic activity, the significance of this phenomenon is not well understood. Granule-bound enzymes, including alkaline phosphatase, are released during the phagocytic process. In addition, the administration of steroids induces an increase in cellular alkaline phosphatase. The significance of this observation is also highly speculative.
In summary, based on the information available to us prior to making the invention herein disclosed, there was little if any reason to suspect the in-vivo activity of the novel biomaterial described below.